2.1. Diltiazem and Its Analogues
Diltiazem, the chemical structure of which is shown in FIG. 1, is an optically active pharmaceutical compound. More specifically, diltiazem, the chemical name of which is (+)-5-[2-(dimethylamino)ethyl]-cis-2,3-dihydro-3-hydroxy-2-(p-methoxypheny l) -1,5-benzothiazapin-4(5)-one acetate (ester), consists of a substituted benzothiazapene wherein both chiral carbon atoms have the S absolute stereo-configuration (H. Inoue et al., U.S. Pat. No. 3,562,257). Diltiazem has proven useful for the treatment of angina due to coronary artery spasm, and for exertional angina. The beneficial therapeutic effects achieved with diltiazem are believed to be derived from the inhibition of calcium ion influx during depolarization of the cell membrane in both cardiac and smooth muscle. Diltiazem is known to prevent coronary artery spasm, both spontaneous and ergonovine provoked, and to decrease peripheral vascular resistance. Diltiazem is marketed by Tanabe and by Marion Laboratories in the United States, where it is sold under the tradename Cardizem.RTM.. Analogues to diltiazem are also known to exist, e.g., wherein the benzothiazapene moiety has a single chlorine substituent on the aromatic ring.
Diltiazem is currently being manufactured via a process similar to that shown in FIG. 2. The first step in the synthetic sequence involves the Lewis acid-catalyzed nucleophilic attack of o-nitrothio- phenol on methyl trans-3-(4-methoxyphenyl)glycidate, as a mixture of enantiomers, to give the threo- compound shown (H. Inoue et al., J. Chem. Soc. Perkin Trans. I, 1725 (1984); H. Inoue et al., J. Chem. Soc. Perkin Trans. I, 421 (1985); H. Inoue et al., U.S. Pat. No. 4,420,628). This threo- compound then needs to be resolved at a subsequent step in the synthetic pathway in order to arrive at the optically active final product (diltiazem).
Alternative production routes to diltiazem utilize o-aminothiophenol in place of o-nitrothiophenol in the step involving opening of and addition to the oxirane ring (S. Nagao et al., U.S. Pat. No. 4,416,819). Such alternative processes also utilize methyl trans-3-(4-methoxyphenyl)glycidate as an intermediate, and thus are subject to improvement by the process of the present invention.